tbuckley/cabot-search huggingface dataset:
Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer
Authors: Rom Leidner, Nelson Sanjuan Silva, Huayu Huang, David Sprott, Chunhong Zheng, Yi-Ping Shih, Amy Leung, Roxanne Payne, Kim Sutcliffe, Julie Cramer, Steven A. Rosenberg, Bernard A. Fox, Walter J. Urba, Eric Tran
Journal: New England Journal of Medicine (2022)

A patient with progressive metastatic pancreatic cancer was treated with a single infusion of 16.2×109 autologous T cells that had been genetically engineered to clonally express two allogeneic HLA-C*08:02-restricted T-cell receptors (TCRs) targeting mutant KRAS G12D expressed by the tumors. The patient had regression of visceral metastases (overall partial response of 72% according to the Response Evaluation Criteria in Solid Tumors, version 1.1); the response was ongoing at 6 months. The engineered T cells constituted more than 2% of all the circulating peripheral-blood T cells 6 months after the cell transfer. In this patient, TCR gene therapy targeting the KRAS G12D driver mutation mediated the objective regression of metastatic pancreatic cancer. (Funded by the Providence Portland Medical Foundation.).
Identifying patient characteristics associated with chemotherapy-induced peripheral neuropathy (CIPN) severity in a phase II clinical trial: A retrospective analysis.
Authors: Wanqing Iris Zhi, Nechama Dreyfus, Andee Dooley, Lauren Piulson, Qing Susan Li, Ting Bao
Journal: Journal of Clinical Oncology (2022)

e24067 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of chemotherapy agents such as platinum, taxanes, vinca alkaloids, and bortezomib. Currently, as no effective prevention strategy is available, chemotherapy delay, reduction, and discontinuation are often necessary due to worsening CIPN. Our retrospective study aimed to identify patient characteristics associated with CIPN during neoadjuvant or adjuvant weekly paclitaxel chemotherapy in patients with early-stage breast cancer. Methods: We retrospectively collected baseline data from the screening phase in a phase IIA trial of weekly acupuncture intervention in women with early-stage breast cancer (ClinicalTrial.gov NCT02364726); the primary outcome was reported previously. Baseline data including age; body mass index (BMI); gender; race; CIPN severity; hemoglobin; hemoglobin A1c; TSH; vitamins B6, B12, and D levels; and anxiety and depression were retrospectively extracted from the electronic medical record (EMR) on the first day of treatment or up to four months prior to chemotherapy initiation. CIPN severity was measured by the Common Terminology Criteria for Adverse Events v4.0. Chemotherapy relative dose density (RDI) was calculated by total chemotherapy dose received divided by the total chemotherapy dose planned; disease recurrence and mortality rate were collected at the time of analysis. Logistic regression was used for statistical analysis. Results: A total of 105 patients’ baseline characteristics were extracted from the EMR. Baseline BMI was associated with CIPN severity (odds ratio [OR] 1.08; 95% confidence interval [CI] 1.01-1.16, p= 0.04). No significant correlations were observed in other covariates. At the median follow-up of 61 months, there were 12 (11.4%) breast cancer recurrences and 8 (7.6%) breast cancer-related deaths. Chemotherapy RDI was associated with disease-free survival (DFS, OR 1.026; 95% CI 1.00-1.05; p= 0.028). Conclusions: In this retrospective analysis, increased BMI was associated with worsening CIPN severity. Chemotherapy RDI was associated with improved DFS. Our findings suggest that baseline BMI may be a risk factor for CIPN. Additionally, suboptimal chemotherapy delivery due to CIPN maybe negatively impact DFS in patients with breast cancer. Further study is warranted to identify risks for CIPN.
Ferrous ions doped calcium carbonate nanoparticles potentiate chemotherapy by inducing ferroptosis
Authors: Yikai Han, Ziliang Dong, Chunjie Wang, Quguang Li, Yu Hao, Zhijuan Yang, Wenjun Zhu, Yunyun Zhang, Zhuang Liu, Liangzhu Feng
Journal: Journal of Controlled Release (2022)
The immunosuppressive landscape of the NOTCH gene family in hepatocellular carcinoma (HCC).
Authors: Hassan Mohammed Abushukair, Leen Mohammad Al-Kraimeen, Anwaar Saeed
Journal: Journal of Clinical Oncology (2022)

e16139 Background: Despite the recent addition of atezolizumab to advanced HCC first-line treatment, response biomarkers are not well studied. The involvement of the NOTCH gene family in HCC tumorigenesis has been previously discussed, yet insights on its effect on the immune microenvironment are still lacking. Methods: We systematically analyzed differentially expressed genes (DEGs) in the KEGG NOTCH pathway across HCC transcriptomics datasets from the HCCDB platform. Immune and prognostic analyses were done using The Cancer Genomic Atlas (TCGA) HCC cohort (n = 372). The TIMER 2.0 tool was used to assess immune infiltration. cBioportal was used for tumor mutational burden (TMB) and microsatellite instability (MSI) correlations. The TIDE tool assessed T cell dysfunction and DEGs efficacy predictive value using the only trial administering atezolizumab (IMvigor210, n = 348). Results: Four DEGs were identified: NCSTN, APH1A, NOTCH3, HDAC2. All four genes were significantly directly associated (spearman’s ρ &gt; 0.1, P &lt; 0.05) with immunosuppressive cells: Tregs, macrophage M2 cells, cancer-associated fibroblasts (CAF), and myeloid-derived suppressor cells (MDSC). HDAC2 was associated with higher T cell dysfunction (z score = 2.07, P = 0.04). High NOTCH3 and low HDAC2 expression served as favorable overall survival (OS) prognostic markers (HR: 0.66, 95% CI: 0.48 - 0.90, P = 0.008 &amp; HR: 1.52, 95% CI: 1.12–2.07, P = 0.006, respectively). Stratification based on the expression of these two genes and strongly associated immunosuppressive cells’ infiltration levels (ρ &gt; 0.5), revealed two unique patients’ subsets with worse OS marked by “low NOTCH3 expression with high CAF levels” and “high HDAC2 expression with high MDSC levels”. Regarding immune checkpoint genes expression, NOTCH3 and HDAC2 expression levels were directly correlated with CTLA-4, PD-1, and TIM-3, whereas NCSTN and APH1A were inversely related with PD-L1, LAG-3, and TIM-3 after correction for multiple hypothesis testing (ρ &gt; 0.2, Q value &lt; 0.05). TMB count was inversely associated with NOTCH3 expression (ρ = - 0.2, P &lt; 0.001), as for the MSI sensor score, NOTCH3 (ρ = -0.29) and APH1A (ρ = 0.29) expression had inverse and direct significant associations, respectively (P &lt; 0.0001). Exploratory subgroup analysis from the IMvigor210 trial on metastatic urothelial carcinoma patients on atezolizumab showed a significant difference in OS favoring low NOTCH3 expression (P = 0.003) and high APH1A expression (P = 0.049). Conclusions: DEGs from the NOTCH family seem to impose an immunosuppressive effect on HCC’s microenvironment. High NOTCH3 and low HDAC2 expression were identified as potential favorable prognostic markers. Interestingly, high NOTCH3 expression translated into worse OS in patients on anti-PD-L1 which could be owed to the inverse relation with TMB and MSI described in our study, thus deserving further translational investigations.
Neutrophil-lymphocyte ratio and prediction of pathological complete response to neoadjuvant treatment in breast cancer.
Authors: Rachel Clarke, Mairi Lucas, Niamh Ryan, Siun Walsh, Sarah Mahon, Catherine Margaret Kelly
Journal: Journal of Clinical Oncology (2022)

e12627 Background: Pathological complete response (pCR) after neoadjuvant therapy in breast cancer is an important prognostic indicator for improved disease free survival. High tumour grade, low ER-status, HER2-positivity predict higher likelihood of a pCR however better predictive biomarkers are needed. The role of the immune system and specifically the presence of tumour infiltrating lymphocytes in increasing response to chemotherapy has been extensively studied across cancer subtypes 2 . We sought to determine if neutrophil-to-lymphocyte ratio (NLR) as a marker of immune inflammatory response could be informative in predicting likelihood of pCR. Methods: We identified a cohort of patients who had received neoadjuvant chemotherapy between 2012 to 2018. We extracted clinical, pathological and laboratory data for each case. A pretreatment peripheral blood test was used to calculate a neutrophil-to-lymphocyte ratio. We used R-studio to analyse our data. The primary objective was to determine if there was an association between NLR and pCR. Statistical analysis was performed to assess whether NLR ratio correlated with pCR. Results: We identified 107 patients who had received NAC for early stage breast cancer during our study period. The mean NLR in the cohort was 2.95 (range 0.76-11.9). 35 (32.7%) patients achieved a pCR. There was no statistically significant different in NLR in those who achieved pCR (n=35) and those who did not (n=72) (p value= 0.75). Patients with triple negative breast cancer (TNBC) had a higher rate of pCR (45.1%), compared to HER2-positive (42.1%) and ER-positive HER2-negative (25.4%). The NLR was not significant in predicting pCR within the separate histological cohorts. Conclusions: NLR did not predict for pathological complete response in our cohort. Further studies into the predictive value of NLR in this setting with larger cohorts are needed. Investigation into the dynamic changes of NLR both pre, post during treatment may provide further insights as may larger cohorts for analysis in each histological subtype.
A targeted gene expression biomarker and association with meningioma outcomes and radiotherapy.
Authors: William Cheng Chen, Abrar Choudhury, Harish Vasudevan, Calixto-Hope C. Lucas, Minh P. Nguyen, Jacob S Young, Theresa Yu, Jason Chan, Nancy Ann Oberheim Bush, Jessica Schulte, Javier Villanueva-Meyer, Steve E. Braunstein, Nicholas A. Butowski, Penny Sneed, Mitchell Berger, Arie Perry, David Solomon, Michael W McDermott, Stephen T. Magill, David R. Raleigh
Journal: Journal of Clinical Oncology (2022)

2007 Background: Improvements in risk stratification of meningioma are needed to guide post-operative management and application of adjuvant therapy. Although profiling of DNA methylation, copy number variants (CNVs), RNA sequencing, and exome sequencing have better elucidated meningioma biology, these approaches have not revealed clinically tractable biomarkers for radiotherapy responses. In this study, we develop and validate a targeted gene expression biomarker to predict meningioma outcomes and benefit from radiotherapy. Methods: Targeted gene expression profiling was performed on a development set of 173 meningiomas (median follow-up 8.1 years) and a validation set of 331 consecutive meningiomas (median follow-up 6.1 years) treated at independent institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). All patients underwent surgery (n = 504) with or without postoperative radiotherapy (n = 73 with radiation). Regularized Cox regression within the development set resulted in a continuous gene expression risk score for local freedom from recurrence (LFFR). The model (34 genes and 7 housekeeping genes) and thresholds for low, intermediate, and high-risk scores were locked and applied to the validation set. Results: The gene expression risk score outperformed WHO grade (validation 5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p = 0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p = 0.01) for LFFR, disease-specific survival, and OS, achieving a negative predictive value for recurrence at 5-years of 93.2%. The biomarker reclassified 35.8% of WHO grade 1 tumors as intermediate or high risk (5-year LFFR/OS 62%/79%), and 18.3% of WHO grade 2-3 tumors as low risk (5-year LFFR/OS 78%/100%). The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and was predictive for LFFR after postoperative radiotherapy, with a hazard ratio of 0.41 for intermediate to high risk propensity-matched meningiomas (95% CI 0.2-0.9, p = 0.0002) versus 0.79 for low risk meningiomas (95% CI 0.1-8.8, p = 0.5182). Conclusions: Targeted gene expression profiling of 504 meningiomas resulted in a biomarker which improved discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and also predicted benefit from radiotherapy.
Fecal metagenome analysis in long-term survivors (LTS) of pancreas cancer.
Authors: Jordan Kharofa, Walaa Hussein, Davendra Sohal, Olugbenga Olanrele Olowokure, Syed A. Ahmad, Sameer H. Patel, Gregory Wilson, Alison Weiss, David Haslam, Senu Apewokin
Journal: Journal of Clinical Oncology (2022)

e16298 Background: Despite improvements in median survival in pancreas adenocarcinoma (PCa), the 5 year overall survival remains less than 10%. Clinical and tumor genomic characteristics have not differentiated PCa long term survivors (LTS) from unselected patients, however specimens in LTS show enhanced tumor immune response. In preclinical studies, fecal transplant experiments from LTS of PCa reveal delayed tumor growth through unknown mechanisms involving the fecal microbiota (Riquelme Cell 2019). However, features of the fecal microbiome in patients with LTS are unknown. Methods: In this cross-sectional study, comprehensive shotgun metagenomics were performed on stool from PCa patients with LTS (n = 16). LTS was defined as &gt; 4 years from pancreatectomy and all therapy without evidence of recurrence. LTS were compared to control patients with PCa who completed pancreatectomy and chemotherapy (n = 6). Stool was sequenced using an Illumina NextSeq500. Raw reads were processed with Kneaddata for trimming, Kracken2 for taxonomic profiling, Bracken for abundance estimation, and Humann3 for metabolic pathway analyses. Statistical analyses were performed in R with MicrobiomeSeq and Phyloseq for comparison of LTS and controls. Results: At diagnosis, the median age of LTS was 60 with a median time from pancreatectomy of 6 years (4-14 years) at donation. The median age of control patients was 65 with a median disease-free survival of 17 months from pancreatectomy. All patients underwent pancreatectomy and chemotherapy prior to sample donation. No material differences were observed in overall microbial diversity for LTS and controls using Shannon/Simpson indexes. The overall composition of bacteria, eukaryotes, viruses and archaea were similar in LTS relative to controls. Lefse analyses revealed significant enrichment of species relative abundance in LTS for the Ruminococacceae family and the Faecalobacterium genus including the Faecalobacterium prausnitzii species. Enriched species in control patients included Clostridium perfringes. Metabolic pathway analyses of the fecal metagenome of LTS revealed several gene families enriched in Faecalobacterium prausnitzii responsible for starch degradation, ribonucleotide biosynthesis, and thiamin degradation as well gene products from Akermannsia mucinophilia representing unknown pathways. Conclusions: Stool from patients cured from PCa share unique microbial features relative to control populations including enrichment of species in the Faecalobacterium genus and Ruminococacceae family . Interestingly, similar species enrichments are observed in metastatic melanoma patients who respond to PD-1 inhibition (Gopalakrishnan Science 2017). Additional studies are needed to explore underlying immune mediated mechanisms in which the fecal microbiota may influence long term survival in PCa.
HGG-04. Intramedullary spinal high grade glioma with ALK fusion and excellent response to targeted treatment with alectinib: case report
Authors: Rina Dvir, Amit Ringel, Ronit Elhasid, Shlomi Constantini, Jonathan Roth
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Intramedullary spinal cord high grade gliomas are rare pediatric tumors , with a grim prognosis. Current therapeutical strategies include a surgical resection if feasible, and radiotherapy. Additional treatments with various chemotherapy agents have had a minor effect and did not change the course of the disease. New molecular targets are a source of hope. Recent molecular evidence regarding high grade infantile hemispheric gliomas describe specific tyrosine kinase receptor fusions or mutations in ALK, ROS, NTRK and MET domains which may lead to therapeutical targets. There is no data regarding these molecular changes in infantile intramedullary high grade gliomas. We present a two year old girl with a cervical high grade glioma with an ALK mutation which received targeted therapy. CASE REPORT: A two year old girl presented with progressive torticollis and hemiparesis. An intramedullary cervical tumor with ill -defined borders was diagnosed. A limited partial excision was performed and the pathological diagnosis was high grade glioma. Within weeks she developed progressive clinical and radiological deterioration. Molecular studies (Oncomine) revealed an ALK fusion (KIF5B) which was confirmed by immunohistochemistry. Treatment with ALK inhibitor alectinib at 150mg daily was initiated. Torticollis resolved within a week, and MRI after 3 months showed outstanding tumor shrinkage with a small residual mass. There were no adverse events to treatment. DISCUSSION: ALK fusion positive high grade glioma has recently been recognized in infants with hemispheric tumors, and a preliminary recent case report demonstrated excellent response to ALK inhibitors. Intramedullary spinal cord high grade gliomas are rare and harbor poor prognosis. This is the first case of ALK fusion glioma of the spine with excellent preliminary response to alectinib. The duration of treatment and long term prognosis is unknown. Molecular investigations can change the approach to pediatric rare CNS tumors.
Associations between seminal microbiota composition and ROS in men with fertility disorders
Authors: S. Mowla, T. Tharakan, L. Farahani, Y.S. Lee, S. Kundu, S. Khanjani, E. Sindi, R. Rai, L. Regan, J.W.A Ramsay, P.R. Bennett, W.S. Dhillo, S. Minhas, D.A. Macintyre, C.N. Jayasena
Journal: European Urology (2022)
Measuring the long commute: Experiences of a multi-ethnic cohort of patients enrolled in a financial reimbursement program for cancer clinical trials.
Authors: Sheyla P Medina, Sylvia Zhang, Elena Nieves, Dana Dornsife, Robert G. Johnson, Darcy V. Spicer, Hala Borno
Journal: Journal of Clinical Oncology (2022)

e18568 Background: Financial reimbursement programs (FRP) aim to address patients’ out-of-pocket expenses associated with clinical trial participation. The study aims to explore patients’ experience in therapeutic clinical trials (TCT) after enrollment in FRP at two academic medical centers in California and identify barriers and opportunities to improve TCT participation. Methods: From May 2019 to January 2020, adult patients with a diagnosis of cancer and eligible for a TCT were recruited from oncology clinics. Eligible participants for the FRP had a household income ≤ 700% of the current HHS Poverty Guidelines. Semi-structured interviews were conducted in patients’ preferred language. Qualitative analysis was performed comparing experiences by site and by preferred language. An iterative process of coding was used to identify themes on interview transcripts. Results: 53 patients were interviewed (20, UCSF; 33, USC). Median age was 59 (IQR 46 - 65) and 59% were female. Nearly half (49%) identified as Latinx/Hispanic compared to 32% Non-Hispanic White, 10% Asian, 4% Black, 1% Native American, and 4% Other. A third were non-English speakers (68% English, 26% Spanish, 6% Korean/Other), 42% had a college education or more, and 55% were retired/unemployed. The majority of patients (66%) had metastatic disease. Patients described their commute to the TCT sites which involved complex logistics and commute time ranging from one hour to 4.5 hours as well as numerous out-of-pocket costs. Prominent barriers to TCT participation included financial toxicity, fears of the process itself or the low likelihood of cure, and systemic factors affecting enrollment. Despite these barriers, most patients would participate in a TCT regardless of financial hardship. Patients proposed modifications to TCTs including decentralization, recruitment strategies, education and peer counseling as well as vouchers and established rates for out-of-pocket expenses. While English-speaking patients were varied on willingness to discuss financial concerns with their doctors, the majority of non-English speakers reported that they would speak with their physician about financial concerns associated with treatment. Conclusions: Patients’ experiences with TCTs demonstrate a combination of financial and logistical stressors that may be lessened by financial reimbursement programs. FRPs have the potential to address inequities in clinical trial access among vulnerable populations.
Responsiveness of the widely used cardiomyocyte cell platforms to simulated ischemia/reperfusion
Authors: B Kiss, ZS Onodi, A Makkos, CS Pelyhe, A Apati, N Varga, D Ree, P Ferdinandy, A Gorbe, Z Varga
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office of Hungary (NKFIA; NVKP-16-1-2016-0017 National Heart Program and OTKA-FK 134751) MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary Ischemic heart disease is the leading cause of death worldwide; therefore, the development of cardioprotective therapies is currently a main focus of research. Cultured cell lines and primary cell cultures play an integral role in cardiovascular research. However, there are many limitations when using these models, including variations in proliferation capacity, uncontrolled stress during cell isolation, poor reproducibility and low translational value. The aim of our study was to test the responsiveness of the most widely used cardiomyocyte platforms to simulated ischemia/reperfusion injury (SI/R) considering the effect of differentiation protocols. Human, rat and mouse cell lines as well as primary cell cultures were used for in vitro viability assay with or without widely used differentiation protocols. The cells were exposed to normoxic or simulated ischemia/reperfusion protocols: a simulated ischemic period of 6 hours was used for the primary and the differentiated cell cultures, while for the non-differentiated cells 16 hours of simulated ischemia followed by 2 hours of reperfusion was applied. The duration of simulated ischemia was determined from preliminary experiments. Viability of the cells was measured by calcein assay. In non-differentiated human AC16 and rat H9C2 cardiac cell lines, cell viability was significantly reduced (50%) by 16h SI / 2h R in contrast, the viability of the mouse HL-1 cell line was not reduced by 16 h SI. In primary rat neonatal cardiac myocytes 6h SI / 2h R caused significant cell death (25%). In primary human iPSC-derived cardiac myocytes 6h SI / 2h R did not result significant injury (10%) whereas 16h did (37%). Responsiveness of different cell types to SI/R ranged between 40-100%. We have shown that the responsiveness of primary cardiac cells and non-differentiated cardiac cell lines is significantly different to simulated ischemia / reperfusion. Differentiation protocols in cell lines markedly affects their response to simulated ischemia / reperfusion. Comparative analyses of different types of cardiomyocytes can provide a good basis for accurate design of in vitro cardioprotective test systems.
Low birth weight is associated with sperm dna fragmentation and assisted reproductive technology outcomes in primary infertile men – results of a cross-sectional study
Authors: L. Boeri, F. Belladelli, E. Pozzi, G. Fallara, M. Raffo, C. Corsini, L. Candela, A. Costa, D. Cignoli, N. Schifano, A. D'Arma, P. Capogrosso, E. Ventimiglia, L. Pagliardini, E. Papaleo, V. Mirone, F. Dehó, F. Montorsi, A. Salonia
Journal: European Urology (2022)